Based on the
       Second Model List of
       Essential Medicines for
       Children 2009
2010
WHO Library Cataloguing-in-Publication Data:

WHO model formulary for children 2010.

Based on the second model list of es...
Acknowledgements                                          WHO Reviewers:
(listed in alphabetical order)                   ...
SELECTED WHO PUBLICATIONS OF RELATED INTEREST

The selection and use of essential medicines.
Report of the WHO Expert Comm...
Contents

Selected WHO Publications of Interest .............................................................................
Abbreviations
ACE         angiotensin-converting enzyme
AIDS        acquired immunodeficiency syndrome
ALP         alkalin...
Introduction

In 2007, the World Health Assembly passed a Resolution titled ‘Better Medicines for Children’. This
resoluti...
Factors influencing paediatric drug therapy

Medicines in children
        It was once said that the moral test of governm...
Of considerable importance, particularly to the general public, is the question of drug administration
and absorption rela...
Plasma protein binding
Drug–protein binding is diminished in neonates due to a lower concentration of plasma proteins,
par...
oxidation is more rapid than in adults. Therefore phenobarbital, phenytoin and theophylline have
shorter half-lives in chi...
How to use the WHO Model Formulary for Children
Medication monographs are listed by section according to the WHO Model Lis...
ATC Code
The Anatomical Therapeutic Chemical (ATC) classification system code designated by WHO to
classify drugs.

Specia...
Interactions with other medications
Details any drug interactions. Potentially hazardous drug interactions are indicated b...
Changes to the WHO Model List of Essential Medicines for Children
Changes made to the 1st List (October 2007) to produce t...
Section 12.3    Enalapril, tablet: 2.5 mg; 5 mg.

Section 15.1    Chlorhexidine, solution: 20% (digluconate).

Section 17 ...
Deletions
Section 6.2.2     Erythromycin, powder for injection: 500 mg (as lactobionate) in vial.
                  Sulfad...
xviii   WHO Model Formulary for Children 2010
SECTION 1:
Anaesthetics


1.1   General anaesthetics and oxygen.................................................. 2
1.2   ...
1        Anaesthetics

1             Anaesthetics

1.1           General anaesthetics and oxygen
To produce a state of pro...
1.1      General anaesthetics and oxygen
Interactions with other medicines (* indicates severe):
  Amitriptyline: increase...
1        Anaesthetics

    Dose:
    Titrate dose to effect.
    Induction and maintenance of anaesthesia (short procedure...
1.1      General anaesthetics and oxygen
References:
Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, Wor...
1        Anaesthetics
Oxygen
ATC code: V03AN01
     Inhalation (medicinal gas)

     Fire hazard. Avoid use of cautery whe...
1.1     General anaesthetics and oxygen
Precautions: Asthma; hypotension; cardiovascular disease; myotonic dystrophy; reco...
1       Anaesthetics
References:
Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp,...
1.2      Local anaesthetics

 Dose:
 Dose needs to be adjusted according to child’s physical status and nature of procedur...
1        Anaesthetics
Lidocaine
ATC code: N01BB02
     Injection: 1%; 2% (hydrochloride) in vial
     Injection for spinal...
1.2      Local anaesthetics
* Atenolol: increased myocardial depression.
  Bupivacaine: increased myocardial depression.
*...
1       Anaesthetics
Adverse effects: Adverse effects generally occur only with excessive dosage or following intravascula...
1.3     Preoperative medication and sedation for short-term procedures

1.3         Preoperative medication and sedation f...
1       Anaesthetics
Adverse effects: Common Dry mouth, blurred vision, photophobia, flushing and dryness of skin,
    ras...
1.3     Preoperative medication and sedation for short-term procedures

 Dose:
 Premedication and sedation for clinical pr...
1        Anaesthetics
Morphine
ATC code: N02AA01
     Injection: 10 mg (as sulfate or hydrochloride) in 1 ml ampoule
Speci...
SECTION 2:
Analgesics, antipyretics, non-steroidal anti-inflammatory
medicines (NSAIMs), medicines used to treat gout and ...
2        Analgesics, antipyretics, NSAIMs, medicines used to treat gout and DMARDs

2             Analgesics, antipyretics...
2.1      Non-opioids and non-steroidal anti-inflammatory medicines (NSAIMs)
Renal impairment: Mild: use lowest effective d...
2        Analgesics, antipyretics, NSAIMs, medicines used to treat gout and DMARDs
Paracetamol
ATC code: N02Be01
     Oral...
2.1    Non-opioids and non-steroidal anti-inflammatory medicines (NSAIMs)
Acetylsalicylic acid
ATC code: N02BA01
  Supposi...
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Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
Medicamentos formulario infantil modelo OMS  2010
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Medicamentos formulario infantil modelo OMS 2010

  1. 1. Based on the Second Model List of Essential Medicines for Children 2009 2010
  2. 2. WHO Library Cataloguing-in-Publication Data: WHO model formulary for children 2010. Based on the second model list of essential medicines for children 2009. 1.Essential drugs. 2.Formularies. 3.Pharmaceutical preparations. 4.Child. 5.Drug utilization. I.World Health Organization. ISBN 978 92 4 159932 0 (NLM classification: QV 55) © World Health Organization 2010 All rights reserved. Publications of the World Health Organization can be obtained from WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; fax: +41 22 791 4857; e-mail: bookorders@who.int). Requests for permission to reproduce or translate WHO publications – whether for sale or for noncommercial distribution – should be addressed to WHO Press, at the above address (fax: +41 22 791 4806; e-mail: permissions@who.int). The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by the World Health Organization to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health Organization be liable for damages arising from its use.
  3. 3. Acknowledgements WHO Reviewers: (listed in alphabetical order) Pedro Albajar-Vinas Jorge Alvar Ezquerra Clinical Editors: Siobhan Crowley Siobhan Andrews1, BPharm GradDipPharmPrac Denis Daumerie Noel Cranswick1, 3, MBBS BMedSc FRACP Margriet den Boer Suzanne Hill2, BMed (Hons) PhD GradDipEpi FAFPHM Tarun Dua Brian Lilley1, BPharm GradDipHospPharm MBA Philippe Duclos Leith Lilley1, BPharm MClinPharm Dirk Engels Kate Milner3, MBBS MPH Olivier Fontaine Courtney Munro1, BPharm GradCertPharmPrac Jose Ramon Franco Minguell Christine Plover1, BPharm (Hons) MClinPharm M. Grzemska David Tickell3, MBBS FRACP Jean Jannin Ivo Kocur 1. The Royal Children’s Hospital, Melbourne Jose Martines 2. Department of Essential Medicines and Pharmaceutical Shanthi Mendis Policies, World Health Organization, Geneva Lulu Muhe 3. Centre for International Child Health, Department of Paediatrics, The University of Melbourne Peter Olumese Ana Padilla Marroquin Reviewers: Juan Pena-Rosas Jonathan Akikusa Pere Perez Simarro Chris Barnes Cathy Roth Naor Bar-Zeev Shekhar Saxena Robert Berkowitz Joanna Tempowski Louise Bordun Wilson Were Penelope Bryant Special thanks to Monique Renevier Thomas Connell for organizing the WHO reviews. Nigel Crawford Andrew Daley Publisher: Andrew Davidson MIMS Australia Trevor Duke (UBM Medica Australia Pty Ltd) James Elder Steve Graham Editors: Amy Gray Matthew Bidgood, BPharm (Hons) PhD Adam Jenney Elizabeth Donohoo, BSc GradCertHlthSc Joshua Kausman Niroshni Gunewardhane, MD Julian Kelly Allyson Harvey, RN BA (Hons) DipBEP Stuart Lewena Valerie Hoa, MPharm (ClinPharm) Sarah McNab Sue Hunter, BVSc (Hons) Rob McDougall Sarah Keen, BPharm Jodie McVernon Olivia Wroth, BVSc DipBEP Paul Monagle Anna Moon Production: Anastasia Pellicano Robert Johanson, BAppSc Rob Roseby Karthick Mani, MCompSc Fiona Russell Corrina Rivett Helen Savoia Daniela Velcich Mike Starr Andrew Steer Business: Garry Warne Margaret Gehrig, Keith Waters BHealthSc (Mgt), AssocDipNursing (Mgt), RN Special thanks to Julian Kelly for Helen Gilmour, organizing the expert reviews. BAppSc (Haem) GradDip (Mktg) WHO Model Formulary for Children 2010 iii
  4. 4. SELECTED WHO PUBLICATIONS OF RELATED INTEREST The selection and use of essential medicines. Report of the WHO Expert Committee (including the WHO Model List of Essential Medicines and the 2nd WHO Model List of Essential Medicines for Children) WHO Technical Report Series, No. 958, 2010 (in print) Pocket book of hospital care for children. 2005 (378 pages) The international pharmacopoeia, fourth edition. Volume 1: general notices; monographs for pharmaceutical substances (A–O) Volume 2: monographs for pharmaceutical substances (P–Z); monographs for dosage forms and radiopharmaceutical preparations; methods of analysis; reagents. 2006 (1500 pages), also available in CD-ROM version Basic tests for drugs: pharmaceutical substances, medicinal plant materials and dosage forms. 1998 (94 pages) Quality assurance of pharmaceuticals: a compendium of guidelines and related materials. Volume 1: 1997 (244 pages) Volume 2: Good manufacturing practices and inspection. 2nd updated edition, 2007 (in print) WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-third report. WHO Technical Report Series, No. 953, 2009 (172 pages) International nonproprietary names (INN) for pharmaceutical substances. Cumulative List no. 13 2010 (available in CD-ROM format only) Further information on these and other WHO publications can be obtained from WHO Press, World Health Organization, 1211 Geneva 27, Switzerland (tel. +41 22 791 3264; fax: +41 22 791 4857; e-mail: bookorders@who.int; order on line: http://www.who.int/bookorders) iv WHO Model Formulary for Children 2010
  5. 5. Contents Selected WHO Publications of Interest ....................................................................................... iv Abbreviations ............................................................................................................................ vi Introduction ............................................................................................................................ vii Guidance for Prescribing in Paediatrics........................................................................................ viii How to Use the WMFC .............................................................................................................. xii Changes to the WHO Model List of Essential Medicines for Children........................................ xv Section 1: Anaesthetics ......................................................................................................... 2 Section 2: Analgesics, antipyretics, non-steroidal anti-inflammatory medicines (NSAIMs), medicines used to treat gout and disease modifying agents in rheumatoid disorders (DMARDs) ........................................................................................... 18 Section 3: Antiallergics and medicines used in anaphylaxis ................................................... 27 Section 4: Antidotes and other substances used in poisonings ............................................... 36 Section 5: Anticonvulsants/antiepileptics .............................................................................. 49 Section 6: Anti-infective medicines ....................................................................................... 64 Section 7: Antimigraine medicines........................................................................................ 240 Section 8: Antineoplastic, immunosuppressives and medicines used in palliative care ........... 246 Section 9: Antiparkinsonism medicines ................................................................................ 295 Section 10: Medicines affecting the blood ............................................................................... 297 Section 11: Blood products and plasma substitutes ................................................................. 308 Section 12: Cardiovascular medicines ..................................................................................... 313 Section 13: Dermatological medicines (topical) ...................................................................... 323 Section 14: Diagnostic agents ................................................................................................. 341 Section 15: Disinfectants and antiseptics ................................................................................ 345 Section 16: Diuretics .............................................................................................................. 352 Section 17: Gastrointestinal medicines ................................................................................... 359 Section 18: Hormones, other endocrine medicines and contraceptives ................................... 374 Section 19: Immunologicals.................................................................................................... 387 Section 20: Muscle relaxants (peripherally-acting) and cholinesterase inhibitors ..................... 431 Section 21: Ophthalmological preparations ............................................................................ 438 Section 22: Oxytocics and antioxytocics ................................................................................. 447 Section 23: Peritoneal dialysis solution ................................................................................... 449 Section 24: Psychotherapeutic medicines ................................................................................ 452 Section 25: Medicines acting on the respiratory tract .............................................................. 461 Section 26: Solutions correcting water, electrolyte and acid-base disturbances......................... 467 Section 27: Vitamins and minerals ......................................................................................... 478 Section 28: Ear, nose and throat conditions in children .......................................................... 488 Section 29: Specific medicines for neonatal care...................................................................... 493 Index ............................................................................................................................ 500 WHO Model Formulary for Children 2010 v
  6. 6. Abbreviations ACE angiotensin-converting enzyme AIDS acquired immunodeficiency syndrome ALP alkaline phosphatase APTT activated partial thromboplastin time ART antiretroviral ATC anatomical therapeutic chemical AUC area under the curve AV atrioventricular BCG Bacillus Calmette–Guérin (vaccine) BNFC British National Formulary for Children BP British Pharmacopoeia BSA body surface area CNS central nervous system CrCl creatinine clearance CSF cerebrospinal fluid ECG electrocardiogram EEG electroencephalogram EMLc Essential Medicines List for Children G6PD glucose 6-phosphate dehydrogenase GFR glomerular filtration rate GI gastrointestinal GORD gastro-oesophageal reflux disease GVHD graft-versus-host disease HIV human immunodeficiency virus Ht height IM intramuscular INR international normalized ratio IV intravenous MB multibacillary leprosy MDI metered dose inhaler MDR-TB multidrug-resistant tuberculosis MMR measles, mumps, rubella MRI magnetic resonance imaging MSSA methicillin-sensitive Staphylococcus aureus MTCT mother-to-child transmission NSAIM non-steroidal anti-inflammatory medicine ORS oral rehydration solution PB paucibacillary leprosy PCP Pneumocystis carinii (Pneumocystis jiroveci) pneumonia PDA patent ductus arteriosus PR per rectum PTB pulmonary tuberculosis PVC polyvinyl chloride SC subcutaneous SIADH syndrome of inappropriate antidiuretic hormone secretion spp. species SSRI selective serotonin reuptake inhibitor TB tuberculosis TSH thyroid stimulating hormone USP United States Pharmacopeia WHO World Health Organization Wt weight vi WHO Model Formulary for Children 2010
  7. 7. Introduction In 2007, the World Health Assembly passed a Resolution titled ‘Better Medicines for Children’. This resolution recognized the need for research and development into medicines for children, including better dosage forms, better evidence and better information about how to ensure that medicines for treating the common childhood diseases are given at the right dose for children of all ages. The World Health Organization has therefore developed a program of work on medicines for children, including the development of a Model List of Essential Medicines for children (EMLc). As an extra resource for health-care workers and national programmes that supply medicines for children, this new edition of the WHO Model Formulary has been prepared, based on the 2nd edition of the EMLc, to provide prescribers with the best information about how to use the medicines included on the List. In developing the WHO Model Formulary for Children, the editors have based decisions on treatment regimens on the best available evidence from clinical studies in children, that have been assessed and evaluated by the WHO Expert Committee on Selection and Use of Essential Medicines. However, as has been found by all authorities in relation to medicines for children, in many cases the recommendations on dose and duration of treatment in children have to be extrapolated from studies in adults and adjusted based on our understanding of the effect of age and development on the absorption, distribution and metabolism and excretion of different medicines in children of different ages. One of the aims of this publication is therefore not only to describe what is known about treatments, but to highlight where more research is needed. An electronic version of the WHO Formulary for Children is also available, intended as a starting point for developing institutional or national formularies. The text of the Formulary can be used by groups who wish to develop their own version, by adapting the text or by adding or deleting entries to align the formulary to their own list of essential medicines. This edition of the WHO Model Formulary is fully compatible with the 2nd List of Essential Medicines for Children, as recommended by the WHO Expert Committee on the Selection and Use of Essential Medicines in March 2009. Comments and suggestions are welcome and should be sent to: The Editor; WHO Model Formulary Medicines Access and Rational Use Department of Essential Medicines and Pharmaceutical Policies World Health Organization 20 Avenue Appia CH-1211 Geneva 27 Email : modelformulary@who.int WHO Model Formulary for Children 2010 vii
  8. 8. Factors influencing paediatric drug therapy Medicines in children It was once said that the moral test of government is how that government treats those who are in the dawn of life, the children; those who are in the twilight of life, the elderly; and those who are in the shadows of life—the sick, the needy and the handicapped.1 Children are among the most vulnerable individuals in any society. Nowhere is this more true than in their access to appropriate health care. As part of the treatment of children, health-care workers need access to drug dosage information. This formulary aims to provide that information universally, to assist in the management of children. The use of medicines in infants and children presents a unique set of challenges to the prescriber. Physiological variances between children and adults, including the ontogeny of organ maturity and body composition, significantly influence the actions, effectiveness and safety of medicines. However, most pharmacokinetic and pharmacodynamic studies provide little, if any, information on drug action in infants and children, because they are usually conducted in adults. Paediatric pharmacology developed initially from the extrapolation of therapeutic practice and experience in adults and the use of “scaled down” adult doses. This practice is clinically successful for the majority of drugs which are relatively non-toxic and have a wide margin between therapeutic and toxic doses. Drugs with a narrow therapeutic margin, such as the aminoglycoside antibiotics and digoxin, require more sophisticated knowledge and individualized dosage regimens. Doses of such agents are scaled by weight or allometrically (wt¾), then modified according to the results of serum drug concentration measurements, if these are available. Over the last two decades, there has been an increased recognition of the necessity to perform studies specifically in children and adolescents. Major national and international approaches, such as those of the European Union and the United States, have resulted in some new information to improve the use of medicines in children. This formulary is the result of the establishment of the WHO Model List of Essential Medicines for Children (EMLc). The list can be accessed at http://www.who.int/selection_medicines/en/. Absorption Oral absorption The gastrointestinal tract, particularly the stomach, undergoes significant changes from birth until around 3 years of age. Before then, the stomach has low levels of acid, and acid-labile drugs, such as the penicillins, show enhanced absorption. On the other hand, this depressed level of acidity may result in reduced absorption of weak acids such as phenobarbitone, phenytoin and rifampicin. The incomplete absorption experienced with these anticonvulsants may necessitate their continued parenteral administration. The delayed gastric emptying seen in neonates and young infants is probably not as important as previously believed. In the first few weeks of life this may be significant, but most sick neonates receive their drugs parenterally. viii WHO Model Formulary for Children 2010
  9. 9. Of considerable importance, particularly to the general public, is the question of drug administration and absorption relative to meals. Current evidence suggests that, with the exception of isoniazid, captopril, rifampicin, phenoxymethylpenicillin and tetracyclines (except doxycycline and minocycline), all medications should be administered with meals to avoid gastrointestinal irritation and to aid compliance. Topical absorption Topical absorption of drugs is enhanced in children and especially in infants. This is a direct result of the relative thinness of the stratum corneum. Absorption may be further enhanced in the presence of burnt or excoriated areas and with occlusive dressings. This has been well documented with the use of corticosteroid creams for eczema and nappy rash in infants, especially when the area treated has been occluded with plastic pants. Rectal absorption Rectal administration may be useful in patients who are vomiting and in infants and young children who are reluctant to take oral medication. The rectal route is not ideal for all drugs. Considerable individual variation in rectal venous drainage, and hence in the extent of drug absorption, can produce either sub-therapeutic or toxic drug levels. Drugs with narrow therapeutic margins should not be administered rectally. One drug which is recommended for rectal administration in children is diazepam for the treatment of seizures. Paracetamol may also be administered rectally; however, the absorption may be erratic and therapeutic levels cannot be guaranteed. Distribution Numerous factors, including body composition, plasma–protein binding and the blood–brain barrier influence drug distribution in the various paediatric age groups. Body composition Total body water and fat composition alter significantly during the transition from birth to adult life. Total body water as a percentage of body weight is approximately 80% at birth, 65% at 12 months and 60% for a young adult male. On the other hand, fat content as a percentage of body weight varies with age, being about 3% in premature infants, 12% in full-term neonates, 30% at 1 year of age and about 18% in the average adult. Therefore, larger mg/kg body weight doses of water-soluble drugs need to be given to neonates and infants to achieve plasma concentrations similar to those seen in adults. However, this has to be balanced against diminished hepatic function and renal elimination before arriving at a final dosage recommendation. WHO Model Formulary for Children 2010 ix
  10. 10. Plasma protein binding Drug–protein binding is diminished in neonates due to a lower concentration of plasma proteins, particularly albumin, and the lower drug-binding capacity of fetal albumin. This may lead to an increase in the fraction of unbound, pharmacologically active drug in the plasma. There may also be competition between endogenous substances, especially free fatty acids and bilirubin, and drugs for albumin-binding sites. However, when drugs administered to neonates are examined in detail, very few highly protein- bound drugs are used. From a practical point of view, highly protein-bound drugs such as phenytoin, sulfonamides, salicylates and diazepam should be given with caution in the presence of hyperbilirubinaemia. In older children, there are several disease states which may affect drug–protein binding, including hepatic disease, nephrotic syndrome, chronic renal failure, cardiac failure and malnutrition. Blood–brain barrier The blood–brain barrier is a permeability barrier between the circulation and the brain cells bathed in cerebrospinal fluid (CSF). The blood–brain barrier is functionally incomplete in the neonate, and certain substances show increased penetration into the brain. One of the most important factors which determine the rate of transport of drugs across the blood–brain barrier is their lipid solubility. This gives rise to increased brain uptake of barbiturates and morphine in infants. As meningitis is a relatively common problem in paediatric practice, the extent to which antimicrobial agents penetrate the CSF is an important consideration. Although some agents penetrate poorly under normal circumstances, in the presence of meningeal inflammation, penetration may be considerably enhanced, so that adequate CSF drug concentrations are attained. Drugs in this category include penicillins, cefalosporins, rifampicin and vancomycin. Drugs which penetrate well even in the absence of meningeal inflammation include chloramphenicol and the combination sulfamethoxazole and trimethoprim. Although the aminoglycosides continue to be used for meningitis caused by Gram-negative organisms, the CSF concentrations achieved are generally low and inconsistent. Higher concentrations can be obtained by direct intrathecal or intraventricular injections, but controversy exists over the efficacy of such routes of administration. The newer cefalosporins, such as cefotaxime, appear to be more appropriate agents in most cases. Metabolism The various metabolic reactions that occur in the mature liver are not fully developed at birth. Cardiac insufficiency and respiratory distress may also contribute to decreased metabolic activity. Lidocaine, phenobarbital, phenytoin and diazepam show decreased metabolism in the neonate, resulting in increased drug half-lives. During the first 15 days of life in premature and full-term babies, decreased metabolism is evident, but this is followed by a dramatic increase. Between 1 and 10 years of age, hepatic microsomal x WHO Model Formulary for Children 2010
  11. 11. oxidation is more rapid than in adults. Therefore phenobarbital, phenytoin and theophylline have shorter half-lives in children than in adults. This more rapid metabolism is almost certainly due to the fact that, during childhood, the liver is larger relative to body weight than in adult life. Allometric scaling may give a better prediction of the metabolic activity of the liver. Excretion Renal function is significantly less developed in premature and full-term neonates than it is in children and adults. Adult values for glomerular filtration rate are reached after about 3 to 6 months of age, while tubular function does not mature fully until after this. Renal function is of particular importance to drug disposition in the neonatal period. Most sick neonates receive antibiotics for suspected or proven infection, and most of these agents are water soluble. In general, the lower the gestational age of the infant, the more prolonged the half-life will be in this period. The rate of elimination increases rapidly during the ensuing weeks, so that half-lives similar to those seen in adults are usually achieved by the end of the first month. The WHO Model Formulary for Children The hope is that this Formulary improves therapies in children by offering the best dosing information for those medicines currently listed on the EMLc. The Formulary is not, however, a substitute for the appropriate use of treatment guidelines, and should be used in conjunction with guidelines such as the WHO Pocket Book of Hospital Care for Children. 1. Humphrey, Hubert H. Speech at the dedication of the Hubert H Humphrey building, Washington, DC, 4 November 1977. http://www.vernalproject.org/IcDQuotes/IcDQuoteA.shtml (accessed 30 March 2008). WHO Model Formulary for Children 2010 xi
  12. 12. How to use the WHO Model Formulary for Children Medication monographs are listed by section according to the WHO Model List of Essential Medicines for Children March 2009. Omission of a particular medication does not necessarily indicate that it is not available or recommended in children; merely that it is not considered an essential medicine for children by WHO. Medicines and dosage forms are listed in alphabetical order within each section and there is no implication of preference for one form over another. Standard treatment guidelines should be consulted for information on appropriate dosage forms. The WHO Model Formulary for Children classifies children by age and doses medicines accordingly, most often in mg/kg. The Formulary is intended for use for children up to 12 years of age. Definition of age ranges Neonate: 0–28 days Infant 1–12 months Child 1–12 years If a maximum dose is listed this provides an indication of the upper dose limit when dosing paediatrics per kilogram. Allowances must be made when using weight as a basis for dosing in oedematous or obese children. In such children the ideal weight for height and age should be used. In many cases, progressive dose adjustments may be required according to the patient’s response. Doses based on surface area are quoted for some drugs. Surface area is calculated by the following equation: Body surface area (m2) = Ht (cm) x Wt (kg) 3600 Mosteller RD. Simplified calculation of body surface area. New England Journal of Medicine, 1987, 317(17):1098 (letter). Explanatory notes for drug monographs: Section and section number This indicates the section and any subsection that the medicine is classified under as per the WHO Model List of Essential Medicines for Children March 2009. A single medication may appear multiple times on the list in different sections for differing indications. Drug Name The generic (non-proprietary) name. Dose Forms The dose form is listed as per the WHO Model List of Essential Medicines for Children March 2009. Some countries may have access to preparations which differ in terms of concentration or dose form. When a medicine is in solution or a mixture the concentration in the medication monograph is expressed as mg/ml to avoid confusion, this may differ from the WHO Model List of Essential Medicines for Children March 2009. xii WHO Model Formulary for Children 2010
  13. 13. ATC Code The Anatomical Therapeutic Chemical (ATC) classification system code designated by WHO to classify drugs. Special Notes Indicate if the medicine is also known by another name, different spelling or abbreviation. Also, notes if there is a WHO age/weight restriction or representative status. Warnings Where there is a significant warning, risk or adverse effect associated with using the medication. Indications Indications for use from the WHO Model List of Essential Medicines for Children March 2009. Contraindications Details of any contraindications to use of the drug. Precautions Details of any precautions or monitoring required. Dose Indication. Route: Age dose and frequency. Alternative route: Age dose and frequency. Renal impairment Advice for use of this drug in these circumstances. Renal impairment is usually divided into three grades: Mild: GFR 20–50 ml/minute or approximate serum creatinine 150–300 micromol/litre Moderate: GFR 10–20 ml/minute or serum creatinine 300–700 micromol/litre Severe: GFR < 10 ml/minute or serum creatinine > 700 micromol/litre Consult specialist texts for further information on use of drugs in renal impairment. Hepatic Impairment Advice for use of this drug in these circumstances. Consult specialist texts for further information on use of drugs in hepatic impairment. Adverse effects Details of adverse effects associated with this medication. Adverse effects have been classified by incidence where possible: Common: > 1% (> 1 in 100 people) Uncommon: 0.1%–1% ( > 1 in 1,000 people and < 1 in 100 people) Rare: < 0.1% (< 1 in 1,000 people) WHO Model Formulary for Children 2010 xiii
  14. 14. Interactions with other medications Details any drug interactions. Potentially hazardous drug interactions are indicated by the symbol * meaning the combined administration of the drugs involved should be avoided, or only taken with caution and appropriate monitoring. Interactions with no symbol do not usually have serious consequences. Notes Includes ancillary information where applicable such as administration instructions, patient advice and storage instructions. References Includes a list of references used to compile this drug monograph. Consult individual references for more information. The presence of an entry on the Essential Medicines List and/or WHO Children’s Formulary carries no assurance as to pharmaceutical quality. It is the responsibility of the relevant national or regional drug regulatory authority to ensure that each product is of appropriate pharmaceutical quality (including stability) and that when relevant, different products are interchangeable. For recommendations and advice concerning all aspects of the quality assurance of medicines see the WHO Medicines web site http://www.who.int/medicines/areas/quality_assurance/en/index.html xiv WHO Model Formulary for Children 2010
  15. 15. Changes to the WHO Model List of Essential Medicines for Children Changes made to the 1st List (October 2007) to produce the 2nd List (March 2009) are listed below. Changes to the List Additions Section 4.2 Acetylcysteine, oral liquid: 10% and 20%. Section 5 Lorazepam, parenteral formulation: 2 mg/ml in 1 ml ampoule; 4 mg/ml in 1 ml ampoule. Section 6.2.1 Cefalexin, powder for reconstitution with water: 125 mg/5 ml; 250 mg/5 ml and solid oral dosage form: 250 mg. Cefotaxime, powder for injection: 250 mg per vial. Ceftazidime, powder for injection: 1 g (as pentahydrate) in vial. Section 6.2.2 Ciprofloxacin, oral liquid: 250 mg/5 ml and solution for IV infusion: 2 mg/ml. Doxycycline, oral liquid: 25 mg/5 ml and 50 mg/5 ml. Section 6.2.4 Amikacin, powder for injection: 100 mg; 500 mg in vial. Section 6.4.2.3 Atazanavir, solid oral dosage form: 100 mg; 150 mg; 300 mg. Lopinavir + ritonavir (LPV/r), tablet (heat stable): 100 mg + 25 mg ; 200 mg + 50 mg. Ritonavir, tablet (heat stable): 25 mg; 100 mg. Lamivudine + nevirapine + stavudine, tablet (dispersible): 30 mg + 50 mg + 6 mg; 60 mg + 100 mg + 12 mg. Lamivudine + nevirapine + zidovudine, tablet: 30 mg + 50 mg + 60 mg. Lamivudine + zidovudine, tablet: 30 mg + 60 mg. Section 6.5.3.1 Artemether + lumefantrine, tablet (dispersible): 20 mg + 120 mg. Section 6.5.4 Sulfadiazine, tablet: 500 mg. Section 8.2 Carboplatin, injection: 50 mg/5 ml; 150 mg/15 ml; 450 mg/45 ml; 600 mg/60 ml. Section 8.4 Amitriptyline, tablet: 10 mg; 25 mg. Cyclizine, injection: 50 mg/ml and tablet: 50 mg. Dexamethasone, injection: 4 mg/ml and tablet: 2 mg. Diazepam, injection: 5 mg/ml and oral liquid: 2 mg/5 ml and rectal solution: 2.5 mg; 5 mg; 10 mg and tablet: 5 mg; 10 mg. Docusate sodium, capsule: 100 mg and oral liquid: 50 mg/5 ml. Hyoscine hydrobromide, injection: 400 micrograms/ml; 600 micrograms/ml and transdermal patches: 1 mg/72 hours. Ibuprofen, oral liquid: 100 mg/5 ml and tablet: 200 mg; 400 mg and 600 mg. Midazolam, injection: 1 mg/ml and 5 mg/ml. Morphine, granules (modified release) (to mix with water): 20 mg; 30 mg; 60 mg; 100 mg; 200 mg and injection: 10 mg/ml and oral liquid: 10 mg/5 ml and tablet (controlled release): 10 mg; 30 mg; 60 mg and tablet (immediate release): 10 mg. Senna, oral liquid: 7.5 mg/5 ml. WHO Model Formulary for Children 2010 xv
  16. 16. Section 12.3 Enalapril, tablet: 2.5 mg; 5 mg. Section 15.1 Chlorhexidine, solution: 20% (digluconate). Section 17 Pancreatic enzymes, age-appropriate formulations and doses including lipase, protease and amylase. Section 17.1 Omeprazole, powder for oral liquid: 20 mg; 40 mg sachets and solid oral dosage form: 10 mg; 20 mg; 40 mg. Section 17.2 Dexamethasone, injection: 4 mg/ml in 1 ml ampoule and oral liquid: 0.5 mg/5 ml; 2 mg/5 ml and solid oral dosage form: 0.5 mg; 0.75 mg; 1.5 mg; 4 mg. Ondansetron, injection: 2 mg base/ml in 2 ml ampoule (as hydrochloride) and oral liquid: 4 mg base/5 ml and solid oral dosage form: Eq 4 mg base; Eq 8 mg base. Section 18.1 Fludrocortisone, tablet: 100 micrograms. Hydrocortisone, tablet: 5 mg; 10 mg; 20 mg. Section 28 Ear, nose and throat conditions in children (new section): Acetic acid, topical: 2%, in alcohol. Budesonide, nasal spray: 100 micrograms per dose. Ciprofloxacin, topical: 0.3% drops. Xylometazoline, nasal spray: 0.05%. Section 29 Specific medicines for neonatal care (new section): Caffeine citrate, injection: 20 mg/ml (equivalent to 10 mg caffeine base/ml) and oral liquid: 20 mg/ml (equivalent to 10 mg caffeine base/ml). Surfactant, suspension for intratracheal instillation: 25 mg/ml or 80 mg/ml. Prostaglandin E, solution for injection: Prostaglandin E: 0.5 mg/ml in alcohol and Prostaglandin E2: 1 mg/ml. Ibuprofen, solution for injection: 5 mg/ml. Amendments to dosage strength and form Section 5 Diazepam, injection: 5 mg/ml in 2 ml ampoule (intravenous or rectal) changed to rectal solution or gel: 5 mg/ml in 0.5 ml; 2 ml and 4 ml tubes. Section 10.2 Heparin sodium, injection: 1000 IU/ml; 5000 IU/ml; 20 000 IU/ml in 1 ml ampoule changed to injection: 1000 IU/ml; 5000 IU/ml in 1 ml ampoule. Section 16 Spironolactone, oral liquid: 1 to 20 mg/ml and tablet: 25 mg changed to oral liquid: 5 mg/5 ml; 10 mg/5 ml; 25 mg/5 ml and tablet: 25 mg. Section 25.1 Budesonide, 50 micrograms per dose (dipropionate); 250 micrograms (dipropi- onate) per dose changed to inhalation (aerosol): 100 micrograms per dose; 200 micrograms per dose. Section 26.2 Potassium chloride, solution: 11.2% in 20 ml ampoule changed to solution for di- lution: 7.5% (equivalent to K+ 1 mmol/ml and Cl- 1 mmol/ml); 15% (equivalent to K+ 2 mmol/ml and Cl- 2 mmol/ml). xvi WHO Model Formulary for Children 2010
  17. 17. Deletions Section 6.2.2 Erythromycin, powder for injection: 500 mg (as lactobionate) in vial. Sulfadiazine, injection: 250 mg (sodium salt) in 4 ml ampoule and tablet: 500 mg. Section 6.2.4 Rifampicin + isoniazid, tablet: 60 mg + 30 mg; 60 mg + 60 mg (for intermittent use three times weekly). Rifampicin + isoniazid + pyrazinamide, tablet: 60 mg + 30 mg + 150 mg. Section 6.4.2.3 Nelfinavir (NFV), oral powder: 50 mg/g and tablet: 250 mg (as mesilate). Section 8.2 Cisplatin, powder for injection: 10 mg; 50 mg in vial. Section 13.5 Dithranol, ointment: 0.1% to 2.0%. Section 17.2 Promethazine, injection: 25 mg (hydrochloride)/ml in 2 ml ampoule and oral liquid: 5 mg (hydrochloride)/5 ml and tablet: 10 mg; 25 mg (hydrochloride). Section 18.5 Insulin injection (soluble), injection: 40 IU/ml in 10 ml vial. Intermediate-acting insulin, injection: 40 IU/ml in 10 ml vial (as compound insulin zinc suspension or isophane insulin). Section 25.2 Caffeine citrate, injection: 20 mg/ml (equivalent to 10 mg caffeine base/ml) and oral liquid: 20 mg/ml (equivalent to 10 mg caffeine base/ml). Section 26.2 Glucose with sodium chloride, 4% glucose, 0.18% sodium chloride (equivalent to Na+ 30 mmol/l, Cl- 30 mmol/l). Potassium chloride, solution: 11.2% in 20 ml ampoule. Moved from complementary to core Section 6.5.2 Amphotericin B, powder for injection: 50 mg in vial. As deoxycholate or liposomal. WHO Model Formulary for Children 2010 xvii
  18. 18. xviii WHO Model Formulary for Children 2010
  19. 19. SECTION 1: Anaesthetics 1.1 General anaesthetics and oxygen.................................................. 2 1.2 Local anaesthetics ........................................................................ 8 1.3 Preoperative medication and sedation for short-term procedures................................................................ 13 WHO Model Formulary for Children 2010 1
  20. 20. 1 Anaesthetics 1 Anaesthetics 1.1 General anaesthetics and oxygen To produce a state of prolonged full surgical anaesthesia reliably and safely, careful administration of a variety of drugs and close monitoring of the patient are required. Anaesthesia should be undertaken by non-specialist personnel only as a last resort, because anaesthetic drugs may be fatal if inappro- priately used. Irrespective of the type of anaesthesia used (i.e. general or regional), it is essential that facilities for intubation and mechanically assisted ventilation are available. Anaesthesia may be induced and maintained with intravenous medications and/or inhalation of a volatile agent (section 1.1). A range of other drugs including local anaesthetics (section 1.2), pre- operative medications (section 1.3), opioid analgesics (section 2.2), muscle relaxants and reversal agents (e.g. cholinesterase inhibitors; section 20) may also be required. Oxygen should be added routinely during anaesthesia with inhalation agents, even when air is used as the carrier, to protect against hypoxia. Halothane ATC code: N01AB01 Inhalation Special Notes: This medicine is listed as a representative of its pharmacological class. Other medicines in the same class may have similar clinical performance and may be selected for local formularies based on availability and price. The information in this monograph only applies to the medicine listed here. Indications: Induction and maintenance of anaesthesia. Contraindications: History of unexplained jaundice or fever following previous exposure to halothane; family history of malignant hyperthermia; raised cerebrospinal fluid pressure; porphyria. Precautions: Anaesthetic history should be carefully taken to determine previous exposure and previous reactions to halothane (fulminant hepatic failure is a rare complication of re-exposure to halothane); avoid use if adequate resuscitation facilities are not available. Dose: Induction of anaesthesia. Inhalation through specifically calibrated vaporizer: Infant or Child initially 0.5% then gradually increase inspired gas concentration to 1.5–2% in oxygen or nitrous oxide-oxygen. Maintenance of anaesthesia. Inhalation through specifically calibrated vaporizer: Infant or Child 0.5–2% in oxygen or nitrous oxide-oxygen. Hepatic impairment: Avoid if history of unexplained pyrexia or jaundice following previous exposure to halothane. Adverse effects: Common Bradycardia, respiratory depression. Uncommon Arrhythmias, hepatitis (may be fatal). 2 WHO Model Formulary for Children 2010
  21. 21. 1.1 General anaesthetics and oxygen Interactions with other medicines (* indicates severe): Amitriptyline: increased risk of arrhythmias and hypotension. * Chlorpromazine: enhanced hypotensive effect. Diazepam: enhanced sedative effect. Enalapril: enhanced hypotensive effect. Epinephrine (adrenaline): risk of arrhythmias. * Fluphenazine: enhanced hypotensive effect. Furosemide: enhanced hypotensive effect. * Haloperidol: enhanced hypotensive effect. Isoniazid: possible potentiation of isoniazid hepatotoxicity. * Levodopa: risk of arrhythmias. Spironolactone: enhanced hypotensive effect. Suxamethonium: enhanced effects of suxamethonium. Vancomycin: hypersensitivity-like reactions can occur with concomitant intravenous vancomycin. Vecuronium: enhanced effects of vecuronium. * Verapamil: enhanced hypotensive effect and AV delay. Notes: Preferred drug if intubation is likely to be difficult. Does not augment salivary or bronchial secretions. References: Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. WHO expert committee on the selection and use of essential medicines. The selection and use of essential medicines: report of the WHO expert committee, October 2007 (including the model list of essential medicines for children). WHO Technical Report Series, 2008, 950 (http://www.who.int/medicines/publications/essentialmeds_committeereports/TRS_950.pdf ). Ketamine ATC code: N01AX03 Injection: 50 mg (as hydrochloride)/ml in 10 ml vial Indications: Induction and maintenance of anaesthesia; analgesia for painful procedures of short duration. Contraindications: Thyrotoxicosis; hypertension; severe cardiac disease; history of cerebrovascular accident, cerebral trauma, intracerebral mass or haemorrhage or other cause of raised intracranial pressure; eye injury and increased intraocular pressure; psychiatric disorders, particularly hallucinations; porphyria. Precautions: Increased cerebrospinal fluid pressure; predisposition to hallucinations or nightmares; supplementary analgesia often required in surgical procedures involving visceral pain pathways (morphine may be used but addition of nitrous oxide will often suffice); administer an antisialogogue to prevent excessive salivation leading to respiratory difficulties; during recovery, patient must remain undisturbed but under observation. SKILLeD TASKS Warn patient or carer about the risk of undertaking tasks requiring attention or coordination, for example riding a bike or operating machinery, for 24 hours. WHO Model Formulary for Children 2010 3
  22. 22. 1 Anaesthetics Dose: Titrate dose to effect. Induction and maintenance of anaesthesia (short procedures), analgesia for short painful procedures. Intravenous injection over at least 60 seconds: Neonate, Infant or Child 1–2 mg/kg produces 5–10 minutes of surgical anaesthesia, adjusted according to response. Intramuscular injection: Neonate 4 mg/kg for 15 minutes of surgical anaesthesia (adjusted according to response). Infant or Child 4–13 mg/kg (4 mg/kg sufficient for some diagnostic procedures), adjusted according to response; 10 mg/kg usually produces 12–25 minutes of surgical anaesthesia. Induction and maintenance of anaesthesia (longer procedures). Continuous intravenous infusion: Neonate initially 0.5–2 mg/kg followed by a continuous intravenous infusion of 500 micrograms/kg/hour adjusted according to response; up to 2 mg/kg/hour may be used to produce deep anaesthesia. Infant or Child initially 0.5–2 mg/kg followed by a continuous intravenous infusion of 0.6–2.7 mg/kg/hour adjusted according to response. Adverse effects: Common Raised blood pressure and pulse rate, raised intracranial pressure, raised intraocular pressure, hypersalivation, increased muscle tone, emergence reactions including hallucinations, restlessness, confusion, irrational behaviour. Uncommon Hypotension, bradycardia. Rare Arrhythmias. Interactions with other medicines (* indicates severe): Amitriptyline: increased risk of arrhythmias and hypotension. * Chlorpromazine: enhanced hypotensive effect. Diazepam: enhanced sedative effect. Enalapril: enhanced hypotensive effect. * Fluphenazine: enhanced hypotensive effect. Furosemide: enhanced hypotensive effect. * Haloperidol: enhanced hypotensive effect. Isoniazid: possible potentiation of isoniazid hepatotoxicity. Spironolactone: enhanced hypotensive effect. Vancomycin: hypersensitivity-like reactions can occur with concomitant intravenous vancomycin. * Verapamil: enhanced hypotensive effect and AV delay. Notes: For IV injection, dilute to a concentration of no more than 50 mg/ml with glucose 5% or sodium chloride 0.9% or water for injection. For continuous IV infusion, dilute to a concentration of 1 mg/ml with glucose 5% or sodium chloride 0.9%; use microdrip infusion for maintenance of anaesthesia. Premedication with an anticholinergic to reduce secretions is recommended before its use in anaesthesia. Anaesthesia persists for up to 15 minutes after a single intravenous injection and is characterized by profound analgesia. Subanaesthetic doses may be used to provide analgesia and sedation for painful procedures of short duration (e.g. dressing of burns, radiotherapeutic procedures, marrow sampling and minor orthopaedic procedures). Recovery is relatively slow and associated with a high incidence of hallucinations and other emergence reactions, such as delirium. 4 WHO Model Formulary for Children 2010
  23. 23. 1.1 General anaesthetics and oxygen References: Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. Rossi S, ed. Australian medicines handbook. Adelaide, Australian Medicines Handbook, 2009. Nitrous oxide ATC code: N01AX13 Inhalation Indications: Maintenance of anaesthesia in combination with other anaesthetic agents and muscle relaxants; analgesia for emergency management of injuries, during postoperative physiotherapy and for refractory pain in terminal illness. Contraindications: Demonstrable collection of air in pleural (pneumothorax), pericardial or peritoneal space; intestinal obstruction; occlusion of middle ear; arterial air embolism; decompression sickness; chronic obstructive airway disease; emphysema. Precautions: Minimize exposure of staff; vitamin B12 deficiency. Dose: Maintenance of light anaesthesia. Inhalation using suitable anaesthetic apparatus: Neonate, Infant or Child up to 66% in oxygen. Analgesia. Inhalation using suitable anaesthetic apparatus: Neonate, Infant or Child up to 50% in oxygen, according to the child’s needs. Adverse effects: Common Nausea and vomiting. Uncommon Arrhythmias. Rare Malignant hyperthermia, after prolonged administration: megaloblastic anaemia, leukopenia, agranulocytosis, neuropathy and myeloneuropathy. Interactions with other medicines (* indicates severe): Amitriptyline: increased risk of arrhythmias and hypotension. * Chlorpromazine: enhanced hypotensive effect. Diazepam: enhanced sedative effect. Enalapril: enhanced hypotensive effect. * Fluphenazine: enhanced hypotensive effect. Furosemide: enhanced hypotensive effect. * Haloperidol: enhanced hypotensive effect. Isoniazid: possible potentiation of isoniazid hepatotoxicity. * Methotrexate: increased antifolate effect (avoid concomitant use). Spironolactone: enhanced hypotensive effect. Vancomycin: hypersensitivity-like reactions can occur with concomitant intravenous vancomycin. * Verapamil: enhanced hypotensive effect and AV delay. Notes: Should not be used as a sole anaesthetic agent due to lack of potency. References: Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. Rossi S, ed. Australian medicines handbook. Adelaide, Australian Medicines Handbook, 2009. WHO Model Formulary for Children 2010 5
  24. 24. 1 Anaesthetics Oxygen ATC code: V03AN01 Inhalation (medicinal gas) Fire hazard. Avoid use of cautery when oxygen is used with ether; reducing valves on oxygen cylinders must not be greased (risk of explosion). Special Notes: Inhalation gas. Indications: Maintain adequate tissue oxygenation in inhalational anaesthesia and other indications for use in neonates and children. Used during resuscitation and in the treatment of respiratory problems requiring supplemental oxygen. Dose: Concentration of oxygen in inspired anaesthetic gases should never be less than 21%, and preferably 30% or above. The concentration required depends on the condition being treated. Renal impairment: No dosage adjustment necessary. Hepatic impairment: No dosage adjustment necessary. Adverse effects: Long-term use of concentrations greater than 80% have a toxic effect on the lungs leading to pulmonary congestion, exudation and atelectasis. Short-term use of 100% is not associated with these toxic effects. The concentration required depends on the condition being treated; if available, monitoring of the oxygen delivered is strongly recommended, as inappropriate concentration may have serious or even lethal effects. Risks include morbidity, brain damage, and especially in pre-term neonates can cause retinopathy with blindness and chronic lung disease. Use of 100% oxygen should not be withheld in an emergency situation. Interactions with other medicines (* indicates severe): * Bleomycin: serious pulmonary toxicity in patients exposed to conventional oxygen concentrations during anaesthesia. Notes: Monitoring of oxygen delivered is strongly recommended. If available, use oxygen analyser to monitor inspired oxygen and pulse oximeter to monitor oxygen saturation. Oxygen should be added routinely during anaesthesia with inhalational agents, even when air is used as the carrier gas, to protect against hypoxia. References: Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Thiopental ATC code: N01AF03 Powder for injection: 0.5 g; 1 g (sodium salt) in ampoule Special Notes: Specialist skills required for administration and supportive management. Indications: Induction of anaesthesia prior to administration of inhalational anaesthetic; anaesthesia of short duration. Contraindications: Inability to maintain airway; hypersensitivity to barbiturates; severe cardiovascular disease; dyspnoea or obstructive respiratory disease; porphyria. 6 WHO Model Formulary for Children 2010
  25. 25. 1.1 General anaesthetics and oxygen Precautions: Asthma; hypotension; cardiovascular disease; myotonic dystrophy; reconstituted solution is highly alkaline: extravasation can result in extensive tissue necrosis and sloughing; intra- arterial injection causes intense pain and may result in arteriospasm; rapid administration may result in severe hypotension and hiccups; renal impairment; hepatic impairment. SKILLeD TASKS Warn patient or carer about the risk of undertaking tasks requiring attention or coordination, for example riding a bike or operating machinery, for 24 hours. Dose: Titrate dose to effect. Induction of anaesthesia, anaesthesia of short duration (< 15–20 minutes). Slow IV injection usually as a 2.5% (25 mg/ml) solution over 10–15 seconds: Neonate initially up to 2 mg/kg, then 1 mg/kg repeated as necessary (maximum total dose 4 mg/kg). Infant or Child initially up to 5 mg/kg, then 1 mg/kg repeated as necessary (maximum total dose 7 mg/kg). Renal impairment: May need to reduce dose in severe impairment; administer slowly. Hepatic impairment: Reduce dose for induction in severe liver disease. Adverse effects: Common Hypotension, transient erythema, injection site reactions, cardiorespiratory depression, myocardial depression, prolonged somnolence and recovery, cough, sneezing, cardiac arrhythmias. Uncommon Laryngospasm, rash, allergic reactions. Rare Anaphylaxis, bronchospasm, haemolytic anaemia. Interactions with other medicines (* indicates severe): Amitriptyline: increased risk of arrhythmias and hypotension. * Chlorpromazine: enhanced hypotensive effect. Diazepam: enhanced sedative effect. Enalapril: enhanced hypotensive effect. * Fluphenazine: enhanced hypotensive effect. Furosemide: enhanced hypotensive effect. * Haloperidol: enhanced hypotensive effect. Isoniazid: possible potentiation of isoniazid hepatotoxicity. Silver sulfadiazine: enhanced effects of thiopental. Spironolactone: enhanced hypotensive effect. Sulfadiazine: enhanced effects of thiopental. Sulfadoxine + pyrimethamine: enhanced effects of thiopental. Sulfamethoxazole + trimethoprim: enhanced effects of thiopental. Vancomycin: hypersensitivity-like reactions can occur with concomitant intravenous vancomycin. * Verapamil: enhanced hypotensive effect and AV delay. Notes: For intravenous injection, dilute to a concentration of 25 mg/ml with water for injection; give over at least 10–15 seconds. Avoid rapid IV injection (may cause hypotension or decreased cardiac output). Induction is rapid and excitement does not usually occur. Thiopental does not have analgesic properties. Monitoring for hypotension and respiratory compromise is required. Lower doses are needed in shock and low cardiac output states. Repeated doses have a cumulative effect especially in neonates where recovery is slower. WHO Model Formulary for Children 2010 7
  26. 26. 1 Anaesthetics References: Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). MIMS Online. Sydney, UBM Medica, 2009 (http://www.mimsonline.com.au/Search/Search.aspx, accessed 10 February 2010). Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. Rossi S, ed. Australian medicines handbook. Adelaide, Australian Medicines Handbook, 2009. WHO expert committee on the selection and use of essential medicines. The selection and use of essential medicines: report of the WHO expert committee, October 2007 (including the model list of essential medicines for children). WHO Technical Report Series, 2008, 950 (http://www.who.int/medicines/publications/essentialmeds_committeereports/TRS_950.pdf ). 1.2 Local anaesthetics Drugs used for conduction anaesthesia (also termed local or regional anaesthesia) reversibly block conduction along nerve fibres. Local anaesthetics have variable properties and a range of uses. These include topical (surface) anaesthesia, local anaesthesia and more specialized anaesthetic procedures requiring higher level technical skills (e.g. nerve blocks and regional, epidural and spinal anaesthesia). Local anaesthetic toxicity Local anaesthetic toxicity is usually due to excessively high plasma concentrations. Therefore, great care should be taken to avoid accidental intravascular injection or unwanted systemic absorption. Facilities for resuscitation should be available at all times. Bupivacaine ATC code: N01BB01 Injection: 0.25%; 0.5% (hydrochloride) in vial Injection for spinal anaesthesia: 0.5% (hydrochloride) in 4 ml ampoule to be mixed with 7.5% glucose solution Special Notes: Bupivacaine is a representative local anaesthetic. Various drugs can serve as alternatives. This medicine is listed as a representative of its pharmacological class. Other medicines in the same class may have similar clinical performance and may be selected for local formularies based on availability and price. The information in this monograph only applies to the medicine listed here. Indications: Infiltration anaesthesia; peripheral and sympathetic nerve block; spinal or epidural anaesthesia (except in dehydrated or hypovolaemic patients); post-operative analgesia. Contraindications: Local inflammation or infection; septicaemia; intravenous regional anaesthesia (e.g. Bier’s block); use in intravenous infusions; spinal or epidural anaesthesia in patients taking anticoagulant therapy or with coagulation disorders; severe anaemia or heart disease; spinal or epidural anaesthesia in dehydrated or hypovolaemic patients; hypersensitivity to amide local anaesthetics. Precautions: Respiratory impairment; hepatic impairment; epilepsy; porphyria; myasthenia gravis. 8 WHO Model Formulary for Children 2010
  27. 27. 1.2 Local anaesthetics Dose: Dose needs to be adjusted according to child’s physical status and nature of procedure. Do not use solutions containing preservatives for spinal, epidural or caudal anaesthesia. Local infiltration. 0.5–2.5 mg/kg as a 0.25% or 0.5% solution; maximum dose 1 ml/kg of 0.25% solution, 0.5 ml/kg of 0.5% solution (2.5 mg/kg). Peripheral nerve block. 0.3–2.5 mg/kg as a 0.25% or 0.5% solution; maximum dose 1 ml/kg of 0.25% solution, 0.5 ml/kg of 0.5% solution. epidural block in surgery, using 0.5% preservative free solution. 1–2.5 mg/kg. Caudal block in surgery, using 0.5% preservative free solution. 1–2.5 mg/kg. NOTe Use lower doses for debilitated patients, or in epilepsy or acute illness. Renal impairment: No dosage adjustment necessary. Hepatic impairment: Avoid (or reduce dose) in severe liver disease. Adverse effects: Adverse effects generally occur only with excessive dosage or following intravascular injection. Common Hypotension, lightheadedness, dizziness, blurred vision, restlessness, tremors, confusion, headache, paraesthesia, somnolence, constipation, nausea, vomiting, oedema, erythema at injection site, petechiae, skin irritation. Uncommon Seizures, arrhythmias. Rare Heart block, cardiac arrest, hypersensitivity reactions, respiratory failure. Interactions with other medicines (* indicates severe): Lidocaine: increased myocardial depression (interaction less likely when lidocaine used topically). Procainamide: increased myocardial depression. * Propranolol: increased risk of bupivacaine toxicity. Quinidine: increased myocardial depression. References: Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). MIMS Online. Sydney, UBM Medica, 2009 (http://www.mimsonline.com.au/Search/Search.aspx, accessed 10 February 2010). Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. Rossi S, ed. Australian medicines handbook. Adelaide, Australian Medicines Handbook, 2009. WHO Model Formulary for Children 2010 9
  28. 28. 1 Anaesthetics Lidocaine ATC code: N01BB02 Injection: 1%; 2% (hydrochloride) in vial Injection for spinal anaesthesia: 5% (hydrochloride) in 2 ml ampoule to be mixed with 7.5% glucose solution Topical forms: 2% to 4% (hydrochloride) Special Notes: Lidocaine is a representative local anaesthetic. Various drugs can serve as alternatives. This medicine is listed as a representative of its pharmacological class. Other medicines in the same class may have similar clinical performance and may be selected for local formularies based on availability and price. The information in this monograph only applies to the medicine listed here. Indications: Local anaesthetic blocks, dental work and spinal anaesthesia. Contraindications: Local inflammation or infection; septicaemia; spinal or epidural anaesthesia in patients taking anticoagulant therapy or with coagulation disorders; severe anaemia or heart disease; spinal or epidural anaesthesia in dehydrated or hypovolaemic patients; hypersensitivity to amide local anaesthetics. Precautions: Bradycardia, impaired cardiac conduction; severe shock; respiratory impairment; renal impairment; hepatic impairment; epilepsy; porphyria; myasthenia gravis. Dose: Dose needs to be adjusted according to child’s physical status and nature of procedure. Use the lowest effective dose and concentration. Do not use solutions containing preservatives for spinal, epidural, caudal or intravenous regional anaesthesia. Local infiltration and peripheral nerve block, using 1% or 2% solution. Child up to 3 mg/kg (0.3 ml/kg of 1% solution and 0.15 ml/kg of 2% solution; maximum dose 200 mg), not repeated within 2 hours. Surface anaesthesia of pharynx, larynx, trachea, using 4% topical solution. Child up to 3 mg/kg (0.075 ml/kg), not repeated within 2 hours. Instil using a jet spray or apply with a swab. Surface anaesthesia of urethra, using 4% topical solution. Child up to 3 mg/kg (0.075 ml/kg), not repeated within 2 hours. Spinal anaesthesia, using 5% solution (with glucose 7.5%). Child up to 3 mg/kg (0.06 ml/kg), not repeated within 2 hours. Renal impairment: Severe: use with caution. Hepatic impairment: Avoid (or reduce dose) in severe liver disease. Adverse effects: Adverse effects generally occur only with excessive dosage or following intravascular injection. Common Hypotension, lightheadedness, dizziness, blurred vision, restlessness, tremors, confusion, headache, paraesthesia, somnolence, constipation, nausea, vomiting, oedema, erythema at injection site, petechiae, skin irritation. Uncommon Seizures, arrhythmias. Rare Heart block, cardiac arrest, hypersensitivity reactions and respiratory failure. Interactions with other medicines (* indicates severe): NOTe Interactions less likely when lidocaine is used topically. * Acetazolamide: hypokalaemia caused by acetazolamide antagonizes action of lidocaine. 10 WHO Model Formulary for Children 2010
  29. 29. 1.2 Local anaesthetics * Atenolol: increased myocardial depression. Bupivacaine: increased myocardial depression. * Furosemide: action of lidocaine antagonized by hypokalaemia caused by furosemide. * Hydrochlorothiazide: action of lidocaine antagonized by hypokalaemia caused by hydrochlorothiazide. Lopinavir: possibly increased plasma concentration of lidocaine. * Procainamide: increased myocardial depression. * Propranolol: increased myocardial depression; increased risk of lidocaine toxicity. * Quinidine: increased myocardial depression. Suxamethonium: neuromuscular blockade enhanced and prolonged. * Timolol: increased myocardial depression. * Verapamil: increased myocardial depression. References: Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). MIMS Online. Sydney, UBM Medica, 2009 (http://www.mimsonline.com.au/Search/Search.aspx, accessed 10 February 2010). Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. Rossi S, ed. Australian medicines handbook. Adelaide, Australian Medicines Handbook, 2009. Lidocaine + Epinephrine (Adrenaline) ATC code: N01BB52 Dental cartridge: 2% (hydrochloride) + epinephrine 1:80 000 Injection: 1%; 2% (hydrochloride) + epinephrine 1:200 000 in vial Special Notes: Do not use in digits and appendages, such as fingers, toes, ears, nose and penis, due to risk of ischaemic necrosis. Mainly used for dental anaesthesia. Indications: Dental anaesthesia; infiltration anaesthesia; peripheral nerve block. Contraindications: LIDOCAINe Local inflammation or infection; septicaemia; spinal or epidural anaesthesia in patients taking anticoagulant therapy or with coagulation disorders; severe anaemia or heart disease; spinal or epidural anaesthesia in dehydrated or hypovolaemic patients; hypersensitivity to amide local anaesthetics. ePINePHRINe Cerebral arteriosclerosis; hypersensitivity to sympathomimetic amines. Precautions: LIDOCAINe Bradycardia; impaired cardiac conduction; severe shock; respiratory impairment; renal impairment; hepatic impairment; epilepsy; porphyria; myasthenia gravis; avoid for ring block of digits or appendages (risk of ischaemic necrosis). ePINePHRINe Hypertension; heart block; heart disease; arrhythmias; cerebrovascular disease; thyroid disease; diabetes mellitus. Dose: Child all ages dose needs to be adjusted according to child’s physical status and nature of procedure. Use the lowest effective dose and concentration. Do not repeat the dose within 2 hours. Maximum dose of lidocaine with epinephrine is 7 mg/kg/dose. Renal impairment: LIDOCAINe Severe: use with caution. Hepatic impairment: LIDOCAINe Avoid (or reduce dose) in severe liver disease. WHO Model Formulary for Children 2010 11
  30. 30. 1 Anaesthetics Adverse effects: Adverse effects generally occur only with excessive dosage or following intravascular injection. Common Hypotension, bradycardia, lightheadedness, dizziness, blurred vision, restlessness, tremors, confusion, headache, paraesthesia, somnolence, constipation, nausea, vomiting, oedema, erythema at injection site, petechiae, skin irritation. Uncommon Seizures, arrhythmias. Rare Heart block, cardiac arrest, hypersensitivity reactions, respiratory failure. Interactions with other medicines (* indicates severe): LIDOCAINe NOTe Interactions less likely when lidocaine is used topically. * Acetazolamide: hypokalaemia caused by acetazolamide antagonizes action of lidocaine. * Atenolol: increased myocardial depression. Bupivacaine: increased myocardial depression. * Furosemide: action of lidocaine antagonized by hypokalaemia caused by furosemide. * Hydrochlorothiazide: action of lidocaine antagonized by hypokalaemia caused by hydrochlorothiazide. Lopinavir: possibly increased plasma concentration of lidocaine. * Procainamide: increased myocardial depression. * Propranolol: increased myocardial depression; increased risk of lidocaine toxicity. * Quinidine: increased myocardial depression. Suxamethonium: neuromuscular blockade enhanced and prolonged. * Timolol: increased myocardial depression. * Verapamil: increased myocardial depression. Notes: Do not administer intravenously or intra-arterially. Before injecting for local anaesthesia, withdraw syringe plunger to make sure that injection is not into a vein or artery. Use preservative free solutions for epidural or caudal use. References: Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). MIMS Online. Sydney, UBM Medica, 2009 (http://www.mimsonline.com.au/Search/Search.aspx, accessed 10 February 2010). Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. Rossi S, ed. Australian medicines handbook. Adelaide, Australian Medicines Handbook, 2009. 12 WHO Model Formulary for Children 2010
  31. 31. 1.3 Preoperative medication and sedation for short-term procedures 1.3 Preoperative medication and sedation for short- term procedures Appropriate premedication is an important consideration for procedures in children requiring conduction or general anaesthesia. Premedication may be used to help manage pain and anxiety and to improve the course of subsequent anaesthesia. A potent analgesic such as morphine (section 2.2) should be administered peri-operatively to patients in severe pain or for analgesia during and after surgery. Atropine ATC code: A03BA01 Injection: 1 mg (as sulfate) in 1 ml ampoule Indications: Preoperative medication to inhibit salivation and secretions; reversal of the muscarinic effects of cholinergic agents such as neostigmine and pyridostigmine; treatment of bradycardia secondary to cholinergic stimulation. Contraindications: Closed-angle glaucoma; myasthenia gravis; prostatic enlargement; severe gastrointestinal inflammatory disease; gastrointestinal obstruction. Precautions: Down syndrome; children; ulcerative colitis; diarrhoea; heart failure; gastrointestinal disorders; hyperthyroidism; cardiac disorders; tachycardia; hypertension; hypoxia; fever and in warm environments (monitor temperature and keep patients cool); constipation; delirium. CHILDReN Children are at increased risk for rapid rise in body temperature due to suppression of sweat gland activity. Large doses may cause paradoxical hyperexcitability. DOWN SyNDROMe Down syndrome children have both increased sensitivity to cardiac effects and mydriasis. Children with Down syndrome also have more secretions and may require atropine more frequently. Dose: Premedication. IV: Child all ages 20 micrograms/kg (max 600 micrograms) immediately before induction of anaesthesia. SC: Neonate 10–15 micrograms/kg 30–60 minutes before induction of anaesthesia. Infant or Child 20 micrograms/kg (minimum dose 100 micrograms, maximum dose 600 micrograms) 30–60 minutes before induction of anaesthesia. IM: Infant or Child 20 micrograms/kg (minimum dose 100 micrograms, maximum dose 600 micrograms) 30–60 minutes before induction of anaesthesia. Reversal of the muscarinic effects of cholinergic agents. IV: Neonate 20 micrograms/kg. Infant or Child 20 micrograms/kg (maximum dose 600 micrograms). Treatment of bradycardia secondary to cholinergic stimulation. IV: Neonate 20 micrograms/kg. Infant or Child 10–20 micrograms/kg (maximum dose 600 micrograms). Renal impairment: Use with caution. No dose adjustment necessary. Hepatic impairment: Use with caution. No dose adjustment necessary. WHO Model Formulary for Children 2010 13
  32. 32. 1 Anaesthetics Adverse effects: Common Dry mouth, blurred vision, photophobia, flushing and dryness of skin, rash, difficulty in micturition, constipation, arrhythmias, tachycardia, palpitations, fever. Uncommon Nausea, vomiting, confusion. Rare Closed-angle glaucoma, seizures. Interactions with other medicines (* indicates severe): NOTe Many drugs have antimuscarinic effects; concomitant use of two or more such drugs can increase adverse effects such as dry mouth, urine retention and constipation. Amitriptyline: increased antimuscarinic adverse effects. Chlorphenamine: increased antimuscarinic adverse effects. Chlorpromazine: increased antimuscarinic adverse effects (but reduced plasma chlorpromazine concentration). Haloperidol: possibly reduced effects of haloperidol. Metoclopramide: antagonism of effects of metoclopramide on gastrointestinal activity. Neostigmine: antagonism of effects of neostigmine. Late unopposed bradycardia may result. Pyridostigmine: antagonism of effects of pyridostigmine. Notes: For IV administration, administer undiluted by rapid IV injection; slow injection may result in paradoxical bradycardia. References: Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). MIMS Online. Sydney, UBM Medica, 2009 (http://www.mimsonline.com.au/Search/Search.aspx, accessed 10 February 2010). Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. Rossi S, ed. Australian medicines handbook. Adelaide, Australian Medicines Handbook, 2009. Diazepam ATC code: N05BA01 Injection: 5 mg/ml in 2 ml ampoule Tablet: 5 mg Special Notes: Drug subject to international control under the Convention on Psychotropic Substances (1971). Diazepam is a representative benzodiazepine. Various drugs can serve as alternatives. Intravenous diazepam can cause airway obstruction and hypoxia in exactly the same way as any other intravenous anaesthetic. This medicine is listed as a representative of its pharmacological class. Other medicines in the same class may have similar clinical performance and may be selected for local formularies based on availability and price. The information in this monograph only applies to the medicine listed here. Indications: Premedication before major or minor surgery (for use in short-term procedures); sedation with amnesia for endoscopic procedures and surgery under local anaesthetic. Contraindications: Central nervous system depression or coma; shock; respiratory depression; acute pulmonary insufficiency; sleep apnoea; severe hepatic impairment; marked neuromuscular respiratory weakness including unstable myasthenia gravis. Precautions: Respiratory disease; muscle weakness and myasthenia gravis; marked personality disorder; hepatic impairment; renal failure; close observation required until full recovery after sedation; porphyria. SKILLeD TASKS Warn patient or carer about the risk of undertaking tasks requiring attention or coordination, for example riding a bike or operating machinery, for 24 hours. 14 WHO Model Formulary for Children 2010
  33. 33. 1.3 Preoperative medication and sedation for short-term procedures Dose: Premedication and sedation for clinical procedures. Oral: Infant or Child 200–300 micrograms/kg (maximum 10 mg) 45–60 minutes prior to procedure. Slow IV (over 2–5 minutes): Infant or Child 100–200 micrograms/kg (maximum 5 mg) immediately before procedure. Renal impairment: Severe: start with small doses; increased cerebral sensitivity. Hepatic impairment: Can precipitate coma. Reduce dose by half. Low doses could be used but a shorter acting agent would be preferable. Adverse effects: Common Drowsiness, sedation, confusion, amnesia, muscle weakness, ataxia, slurred speech, pain on intravenous injection. Uncommon Respiratory depression, hypotension, paradoxical insomnia, excitability, hallucinations and aggression, injection pain and thrombophlebitis. Rare Blood dyscrasias including neutropenia, agranulocytosis, anaemia, leukopenia and thrombocytopenia. Interactions with other medicines (* indicates severe): Amitriptyline: enhanced sedative effect. Chlorphenamine: enhanced sedative effect. Chlorpromazine: enhanced sedative effect. Codeine: enhanced sedative effect. Enalapril: enhanced hypotensive effect. Furosemide: enhanced hypotensive effect. Haloperidol: enhanced sedative effect. Halothane: enhanced sedative effect. Isoniazid: metabolism of diazepam inhibited. Ketamine: enhanced sedative effect. Morphine: enhanced sedative effect. Nitrous oxide: enhanced sedative effect. Phenytoin: plasma phenytoin concentrations possibly increased or decreased by diazepam. Rifampicin: metabolism of diazepam accelerated (reduced plasma concentration). * Ritonavir: plasma concentration possibly increased by ritonavir (risk of extreme sedation and respiratory depression; avoid concomitant use). Spironolactone: enhanced hypotensive effect. Thiopental: enhanced sedative effect. Notes: Do not use via intramuscular injection as absorption is slow and erratic; route should only be used if oral or intravenous administration not possible. Slow intravenous injection into large vein reduces risk of thrombophlebitis. Resuscitation equipment must be available. References: Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). MIMS Online. Sydney, UBM Medica, 2009 (http://www.mimsonline.com.au/Search/Search.aspx, accessed 10 February 2010). Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. Rossi S, ed. Australian medicines handbook. Adelaide, Australian Medicines Handbook, 2009. WHO Model Formulary for Children 2010 15
  34. 34. 1 Anaesthetics Morphine ATC code: N02AA01 Injection: 10 mg (as sulfate or hydrochloride) in 1 ml ampoule Special Notes: Risk of ten times overdose in small children. extreme care required with dose calculation and preparation. Drug subject to international control under the Single Convention on Narcotic Drugs (1961). Indications: Preoperative sedative and analgesic. Contraindications: Respiratory depression; severe respiratory disease; CNS depression; risk of paralytic ileus; raised intracranial pressure or head injury (affects pupillary responses vital for neurological assessment); avoid injection in phaeochromocytoma. Precautions: Renal impairment; hepatic impairment; dependence (severe withdrawal symptoms if withdrawn abruptly); hypothyroidism; convulsive disorders; decreased respiratory reserve and acute asthma; hypotension; prostatic hypertrophy; overdosage. SKILLeD TASKS Warn patient or carer about the risk of undertaking tasks requiring attention or coordination, for example riding a bike or operating machinery, for 24 hours. Dose: Sedation and analgesia for procedures. IV: Infant or Child 0.05–0.1 mg/kg 5 minutes before the procedure. Maximum dose 15 mg. IM: Infant or Child 0.1 mg/kg 20 minutes before the procedure. Maximum dose 15 mg. Only use IM route for premedication if patient has no IV access and there is adequate respiratory monitoring available. Renal impairment: Moderate to severe: reduce dose or avoid; increased and prolonged effect; increased cerebral sensitivity. Hepatic impairment: Avoid or reduce dose; may precipitate coma. Adverse effects: Common Nausea, vomiting, constipation, lightheadedness, dizziness, sedation, sweating, dysphoria, euphoria, dry mouth, anorexia, spasm of urinary and biliary tract, pruritus, rash, postural hypotension, miosis. Uncommon Respiratory depression (dose related), bradycardia, tachycardia, palpitations. Rare Syndrome of inappropriate antidiuretic hormone secretion (SIADH), anaphylaxis. Interactions with other medicines (* indicates severe): Amitriptyline: possibly increased sedation. Chlorpromazine: enhanced sedative and hypotensive effect. Ciprofloxacin: avoid premedication with morphine (reduced plasma ciprofloxacin concentration) when ciprofloxacin used for surgical prophylaxis. Diazepam: enhanced sedative effect. Haloperidol: enhanced sedative and hypotensive effect. Metoclopramide: antagonism of effect of metoclopramide on gastrointestinal activity. * Ritonavir: possibly increases plasma concentration of morphine. Notes: For intravenous administration, administer slowly over 5 minutes. Risk of ten times overdose in small children. References: Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). MIMS Online. Sydney, UBM Medica, 2009 (http://www.mimsonline.com.au/Search/Search.aspx, accessed 10 February 2010). Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. Rossi S, ed. Australian medicines handbook. Adelaide, Australian Medicines Handbook, 2009. 16 WHO Model Formulary for Children 2010
  35. 35. SECTION 2: Analgesics, antipyretics, non-steroidal anti-inflammatory medicines (NSAIMs), medicines used to treat gout and disease modifying agents in rheumatoid disorders (DMARDs) 2.1 Non-opioids and non-steroidal anti-inflammatory medicines (NSAIMs).................................................................... 18 2.2 Opioid analgesics ........................................................................ 22 2.3 Medicines used to treat gout ........................................................ 25 2.4 Disease modifying agents used in rheumatoid disorders (DMARDs) .................................................................. 25 WHO Model Formulary for Children 2010 17
  36. 36. 2 Analgesics, antipyretics, NSAIMs, medicines used to treat gout and DMARDs 2 Analgesics, antipyretics, non-steroidal anti-inflammatory medicines (NSAIMs), medicines used to treat gout and disease modifying agents in rheumatoid disorders (DMARDs) Pain management in children In general terms, principles for drug management of pain in children follow the WHO Analgesic Ladder with the following recommendations for increasing pain: • mild pain: non-opioid with or without non-steroidal anti-inflammatory medicine (NSAIM) and adjuvant • moderate pain: mild opioid with non-opioid, NSAIM and adjuvant • severe pain: strong opioid with non-opioid, NSAIM and adjuvant, with or without specialist techniques. Non-drug strategies are also an important part of managing pain in children. 2.1 Non-opioids and non-steroidal anti-inflammatory medicines (NSAIMs) Non-opioid analgesics include paracetamol and NSAIMs (section 2.1). These are particularly suitable for musculoskeletal pain. Combining a non-opioid with an opioid analgesic can provide more effective analgesia than either medication alone. Ibuprofen ATC code: M01Ae01 Tablet: 200 mg; 400 mg Special Notes: WHO age/weight restriction: > 3 months. Indications: Mild to moderate pain. Contraindications: Hypersensitivity (including asthma, angioedema, urticaria or rhinitis) to acetylsalicylic acid or any other NSAIM; active peptic ulceration or upper gastrointestinal bleeding; severe renal failure, hepatic failure or cardiac failure. Precautions: Asthma; cardiac disease; volume depletion, such as in gastroenteritis or dehydration (increased risk of renal impairment); concomitant use of drugs that increase risk of bleeding; previous peptic ulceration; coagulation defects; allergic disorders; renal impairment; hepatic impairment. Dose: Mild to moderate pain. Oral: Infant or Child over 3 months 5–10 mg/kg three or four times daily with or after food. Maximum daily dose is 40 mg/kg/day. 18 WHO Model Formulary for Children 2010
  37. 37. 2.1 Non-opioids and non-steroidal anti-inflammatory medicines (NSAIMs) Renal impairment: Mild: use lowest effective dose and monitor renal function; sodium and water retention may occur as may deterioration in renal function possibly leading to renal failure. Moderate to severe: avoid. Hepatic impairment: Use with caution: increased risk of gastrointestinal bleeding and can cause fluid retention; avoid in severe liver disease. Adverse effects: Common Nausea, diarrhoea, dyspepsia, headache, dizziness, fluid retention, raised blood pressure, gastrointestinal ulceration and bleeding. Uncommon Rash, urticaria, photosensitivity, renal impairment. Rare Angioedema, bronchospasm, hepatic damage, alveolitis, pulmonary eosinophilia, pancreatitis, visual disturbances, erythema multiforme (Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell syndrome), colitis, aseptic meningitis. Interactions with other medicines (* indicates severe): * Acetylsalicylic acid: avoid concomitant use (increased adverse effects). * Ciclosporin: increased risk of nephrotoxicity. Dexamethasone: increased risk of gastrointestinal bleeding and ulceration. Digoxin: possibly exacerbation of heart failure, reduced renal function and increased plasma digoxin concentration. Enalapril: antagonism of hypotensive effect, increased risk of renal impairment. * Fluoxetine: increased risk of bleeding. Furosemide: risk of nephrotoxicity of ibuprofen increased; antagonism of diuretic effect. Heparin: possibly increased risk of bleeding. Hydrocortisone: increased risk of gastrointestinal bleeding and ulceration. * Levofloxacin: possibly increased risk of convulsions. * Lithium: reduced excretion of lithium (increased risk of toxicity). * Methotrexate: excretion of methotrexate reduced (increased risk of toxicity). * Ofloxacin: possible increased risk of convulsions. Penicillamine: possible increased risk of nephrotoxicity. * Phenytoin: effect of phenytoin possibly enhanced. Prednisolone: increased risk of gastrointestinal bleeding and ulceration. Propranolol: antagonism of hypotensive effect. Ritonavir: plasma concentration possibly increased by ritonavir. Spironolactone: risk of nephrotoxicity of ibuprofen increased; antagonism of diuretic effect; possibly increased risk of hyperkalaemia. * Warfarin: anticoagulant effect possibly enhanced. Zidovudine: increased risk of haematological toxicity. Notes: Give with or after food. References: Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. Kemp CA, McDowell JM. Paediatric pharmacopoeia. 13th ed. Melbourne, Royal Children’s Hospital, 2002. MIMS Online. Sydney, UBM Medica, 2009 (http://www.mimsonline.com.au/Search/Search.aspx, accessed 10 February 2010). Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. WHO expert committee on the selection and use of essential medicines. The selection and use of essential medicines: report of the WHO expert committee, October 2007 (including the model list of essential medicines for children). WHO Technical Report Series, 2008, 950 (http://www.who.int/medicines/publications/essentialmeds_committeereports/TRS_950.pdf ). WHO Model Formulary for Children 2010 19
  38. 38. 2 Analgesics, antipyretics, NSAIMs, medicines used to treat gout and DMARDs Paracetamol ATC code: N02Be01 Oral liquid: 25 mg/ml Suppository: 100 mg Tablet: 100 mg to 500 mg Special Notes: Also referred to as acetaminophen. Not recommended for anti-inflammatory use due to lack of proven benefit. Indications: Mild to moderate pain; fever. Precautions: Hepatic impairment; renal impairment; overdosage. Dose: Mild to moderate pain, fever. Oral, rectal: Neonate 10 mg/kg every 6–8 hours as necessary. Maximum 4 doses in 24 hours. If neonate is jaundiced, a 5 mg/kg dose is suitable. Infant or Child 15 mg/kg, up to 1 g, every 4–6 hours as necessary. Maximum 4 doses, or 4 g, in 24 hours. NOTe Infants under 3 months should not be given paracetamol unless advised by a doctor. Hepatic impairment: Dose related toxicity; avoid large doses. Adverse effects: Rare Rash, hypersensitivity, neutropenia, thrombocytopenia, pancytopenia. HePATOTOXICITy Hepatotoxicity (and less frequently renal damage) can occur after paracetamol overdosage. Children in the following situations may be at an increased risk of liver damage from paracetamol overdosage: malnourished, obese, febrile illness, prolonged course, not eaten for a few days or taking liver enzyme inducing drugs. Refer to section 4.2 for more information on paracetamol toxicity. Interactions with other medicines (* indicates severe): Metoclopramide: increased absorption of paracetamol. Warfarin: prolonged regular use of paracetamol possibly enhances anticoagulant effect. Notes: Shake suspension well before use. References: Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. MIMS Online. Sydney, UBM Medica, 2009 (http://www.mimsonline.com.au/Search/Search.aspx, accessed 10 February 2010). Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. Rossi S, ed. Australian medicines handbook. Adelaide, Australian Medicines Handbook, 2009. WHO expert committee on the selection and use of essential medicines. The selection and use of essential medicines: report of the WHO expert committee, October 2007 (including the model list of essential medicines for children). WHO Technical Report Series, 2008, 950 (http://www.who.int/medicines/publications/essentialmeds_committeereports/TRS_950.pdf ). 20 WHO Model Formulary for Children 2010
  39. 39. 2.1 Non-opioids and non-steroidal anti-inflammatory medicines (NSAIMs) Acetylsalicylic acid ATC code: N02BA01 Suppository: 50 mg to 150 mg Tablet: 100 mg to 500 mg Do not use acetylsalicylic acid in children who have or who are recovering from chickenpox (varicella), influenza, acute febrile illness or flu symptoms due to the rare association with Reye’s syndrome. During treatment with acetylsalicylic acid, changes in behaviour may be an early sign of Reye’s syndrome. Patients and carers should be instructed to contact the health-care provider if these symptoms develop. Special Notes: Also referred to as aspirin. Indications: Management of rheumatic fever, juvenile arthritis and Kawasaki disease. Contraindications: Hypersensitivity (including asthma, angioedema, urticaria or rhinitis) to acetylsalicylic acid or any other NSAIM; for simple analgesia and antipyrexia in children under 16 years (risk of Reye syndrome); active peptic ulceration; haemophilia and other bleeding disorders; hepatic failure. Precautions: Asthma; uncontrolled hypertension; concomitant use of drugs that increase risk of bleeding; previous peptic ulceration; G6PD deficiency; dehydration; renal impairment; hepatic impairment. Dose: Administer with or after food. Juvenile arthritis, rheumatic fever. Oral: Infant or Child up to 130 mg/kg daily in 5–6 divided doses in acute conditions; 80–100 mg/kg daily in divided doses for maintenance. Kawasaki disease. Oral: Neonate initially 8 mg/kg four times daily until afebrile, followed by 5 mg/kg once daily for 6–8 weeks. If no evidence of coronary lesions after 8 weeks, discontinue treatment or seek expert advice. Infant or Child initially 7.5–12.5 mg/kg four times daily until afebrile, followed by 2–5 mg/kg once daily for 6–8 weeks. If no evidence of coronary lesions after 8 weeks, discontinue treatment or seek expert advice. Renal impairment: Increased risk of bleeding and acetylsalicylic acid induced renal impairment. Severe: avoid; increased risk of sodium and water retention; deterioration in renal function; gastrointestinal bleeding. Hepatic impairment: Avoid in severe hepatic impairment; increased risk of gastrointestinal bleeding. Adverse effects: Common Nausea, dyspepsia, gastrointestinal ulceration or bleeding, tinnitus, vertigo, confusion, increased bleeding time. Uncommon Hypersensitivity reactions including angioedema, bronchospasm and rash (including Stevens-Johnson syndrome), iron deficiency anaemia, renal impairment, oesophageal ulceration. Rare Major haemorrhage (including gastrointestinal, subconjunctival or other), blood dyscrasias, oedema, myocarditis, Reye syndrome with subsequent encephalopathy and severe hepatic injury. Interactions with other medicines (* indicates severe): Dexamethasone: increased risk of gastrointestinal bleeding and ulceration; dexamethasone reduces plasma salicylate concentration. WHO Model Formulary for Children 2010 21

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